An organ transplantation outcomes have improved the demand for this treatment is steadily increasing. If we are to continue this progress, two crucial issues must be solved: how can the supply of donor organ be improved and how can we induce specific and long lasting tolerance to replace non specific suppression. Induction of specific tolerance in xenotransplantation can potentially solve these issues.
The major axis of this project is to try to induce specific tolerance in xenotransplantation by exploiting the fact that B Lymphocytes can now be subdivided into subsets performing different functions.
The major barrier to xenotransplantation is the presence of preformed antibodies, mostly of the IgM type, which recognise glycoproteins or glycolipids from the xenograft. These preformed antibodies in the rat-guinea-pig model seem to be synthesised by the B-l subset. Using treatments by monoclonal anti-mu or anti-delta antibodies, we can manipulate, eliminate or enhance B cell subsets. Therefore we shall attempt to delete the mature B cell subset. We shall then expose the reconstituting immune system to xenoantigens. Immature B Lymphocytes are specially sensitive to tolerance induction. The state of the immune system will then be checked by injecting xenoantigens mixed with adjuvant and xenografts will be performed. All these studies will need the measure of the life span and apoptotic mechanisms of the different B cell subsets. We shall also make use of the finding that thymic epithelium grafts in able to induce transplantation tolerance.
We propose also to apply the concepts and the tools described above to analyze the autoimmune diabetes of NOD mice which are a model for human insulin dependent diabetes mellitus (IDDM). While it is clear that the destruction of beta cells in pancreas is mediated by T Lymphocytes, it has been observed recently that treatment of neonatal NOD mice with anti-mu antibodies prevents the occurrence of diabetes. This suggest that B cells can somehow participate in the initiation of the disease. We shall try to identify the nature of the guilty subset and to understand the role of this subset in diabetes. Several companies are interested by this programme but they think that more basic research is needed before they bring supply to this project. All the teams involved in this project have been cooperating for a long time, mainly through bilateral interactions. They want now to establish a solid European network exploiting some of the most recent findings and concepts of fundamental immunology in order to manipulate specifically the immune response directed against xenografts and autoantigens.
Funding SchemeCSC - Cost-sharing contracts
901 87 Umeaa